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T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Here, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class II–restricted epitopes, we found that myosin heavy chain α (MYHCA) was a dominant cardiac antigen triggering post-MI CD4⁺ T cell activation in Balb/c mice. Transferred MYHCA_614–629-specific CD4⁺ T cells (TCR-M cells) selectively accumulated in the myocardium and mediastinal lymph nodes (med-LNs) of infarcted mice, acquired a Treg phenotype with a distinct prohealing gene expression profile, and mediated cardioprotection. Myocardial Tregs were also detected in autopsy samples from patients who had had a MI. Noninvasive PET/CT imaging using a CXCR4 radioligand revealed …